Seizures, benign familial infantile, 5

Summary

Seizures, benign familial infantile, 5 (MONDO:0014903) is a disease caused by SCN8A (GenCC Strong), with 3 cohort genes. The dominant Reactome pathway is Interaction between L1 and Ankyrins (3 cohort genes).

At a glance

• Causal gene: SCN8A (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 84

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	seizures, benign familial infantile, 5
Mondo ID	MONDO:0014903
OMIM	617080
DOID	DOID:0081118
UMLS	C4310728
MedGen	934695
GARD	0016506
Is cancer (heuristic)	no

Also known as: benign familial infantile epilepsy caused by mutation in SCN8A · BFIS5 · SCN8A benign familial infantile epilepsy · seizures, benign familial infantile, 5 · seizures, benign familial infantile, 5; BFIS5 · seizures, benign familial infantile, type 5

Data availability: 84 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome › infantile epilepsy syndrome › benign partial infantile seizures › benign familial infantile epilepsy › seizures, benign familial infantile, 5

Related subtypes (4): seizures, benign familial infantile, 2, seizures, benign familial infantile, 3, seizures, benign familial infantile, 4, benign familial neonatal-infantile seizures 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

84 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 14 conflicting classifications of pathogenicity, 14 likely pathogenic, 10 pathogenic/likely pathogenic, 9 benign, 6 pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
205963	NM_004519.4(KCNQ3):c.688C>T (p.Arg230Cys)	KCNQ3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
464912	NM_001040142.2(SCN2A):c.4766A>G (p.Tyr1589Cys)	SCN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342316	NM_001330260.2(SCN8A):c.2901+2T>C	SCN8A	Pathogenic	criteria provided, single submitter
135651	NM_001330260.2(SCN8A):c.2549G>A (p.Arg850Gln)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399415	NM_001330260.2(SCN8A):c.632T>G (p.Val211Gly)	SCN8A	Pathogenic	criteria provided, single submitter
1465027	NM_001330260.2(SCN8A):c.424A>G (p.Ile142Val)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207123	NM_001330260.2(SCN8A):c.4472C>T (p.Ala1491Val)	SCN8A	Pathogenic	criteria provided, single submitter
207131	NM_001330260.2(SCN8A):c.5614C>T (p.Arg1872Trp)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
208500	NM_001330260.2(SCN8A):c.2300C>T (p.Thr767Ile)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253195	NM_001330260.2(SCN8A):c.4447G>A (p.Glu1483Lys)	SCN8A	Pathogenic	criteria provided, multiple submitters, no conflicts
253297	NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln)	SCN8A	Pathogenic	reviewed by expert panel
3375774	NM_001330260.2(SCN8A):c.4774G>T (p.Val1592Leu)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420831	NM_001330260.2(SCN8A):c.5606T>C (p.Met1869Thr)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430208	NM_001330260.2(SCN8A):c.5360C>A (p.Thr1787Asn)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
574400	NM_001330260.2(SCN8A):c.2945C>T (p.Ala982Val)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
642701	NM_001330260.2(SCN8A):c.3944T>C (p.Val1315Ala)	SCN8A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4796515	NM_001330260.2(SCN8A):c.212del (p.Asp71fs)	LOC114803470	Likely pathogenic	criteria provided, single submitter
1334502	NM_001330260.2(SCN8A):c.2824_2825insA (p.Trp942Ter)	SCN8A	Likely pathogenic	criteria provided, single submitter
1505439	NM_001330260.2(SCN8A):c.5605A>G (p.Met1869Val)	SCN8A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
162015	NM_014191.4(SCN8A):c.667A>G (p.Arg223Gly)	SCN8A	Likely pathogenic	criteria provided, single submitter
2501688	NM_001330260.2(SCN8A):c.4841C>A (p.Thr1614Asn)	SCN8A	Likely pathogenic	criteria provided, single submitter
2582519	NM_001330260.2(SCN8A):c.2935_2936delinsAA (p.Ser979Asn)	SCN8A	Likely pathogenic	criteria provided, single submitter
2852598	NM_001330260.2(SCN8A):c.4880T>C (p.Ile1627Thr)	SCN8A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024271	NC_000012.11:g.52199766_52388207del	SCN8A	Likely pathogenic	criteria provided, single submitter
3235701	NM_001330260.2(SCN8A):c.445A>G (p.Met149Val)	SCN8A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3238793	NM_001330260.2(SCN8A):c.677G>C (p.Arg226Pro)	SCN8A	Likely pathogenic	criteria provided, single submitter
3238817	NM_001330260.2(SCN8A):c.4442T>A (p.Met1481Lys)	SCN8A	Likely pathogenic	criteria provided, single submitter
3370500	NM_001330260.2(SCN8A):c.4784T>C (p.Leu1595Pro)	SCN8A	Likely pathogenic	criteria provided, single submitter
689732	NM_014191.4(SCN8A):c.676A>G (p.Arg226Gly)	SCN8A	Likely pathogenic	criteria provided, single submitter
689734	NM_014191.4(SCN8A):c.697G>A (p.Val233Ile)	SCN8A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SCN8A	Strong	Autosomal dominant	seizures, benign familial infantile, 5	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
KCNQ3	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ3	Orphanet:306	Self-limited infantile epilepsy
KCNQ3	Orphanet:307	Juvenile myoclonic epilepsy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	gencc,clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
KCNQ3	HGNC:6297	ENSG00000184156	O43525	Potassium voltage-gated channel subfamily KQT member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
KCNQ3	Potassium voltage-gated channel subfamily KQT member 3	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	3	111.5×	7e-07

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
KCNQ3	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ3, Ion_trans_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	3
middle temporal gyrus	2
postcentral gyrus	1
cerebellar vermis	1
ganglionic eminence	1
lateral nuclear group of thalamus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
KCNQ3	180	broad	marker	ganglionic eminence, lateral nuclear group of thalamus, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN2A	2,810
KCNQ3	2,665
SCN8A	2,120

Intra-cohort edges

A	B	Sources
KCNQ3	SCN2A	string_interaction
KCNQ3	SCN8A	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ3	O43525	16
SCN8A	Q9UQD0	7
SCN2A	Q99250	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	3	368.4×	3e-07	SCN8A, SCN2A, KCNQ3
L1CAM interactions	3	120.2×	4e-06	SCN8A, SCN2A, KCNQ3
Axon guidance	3	45.1×	4e-05	SCN8A, SCN2A, KCNQ3
Nervous system development	3	42.9×	4e-05	SCN8A, SCN2A, KCNQ3
Phase 0 - rapid depolarisation	2	230.7×	7e-05	SCN8A, SCN2A
Cardiac conduction	2	72.5×	6e-04	SCN8A, SCN2A
Developmental Biology	3	14.5×	7e-04	SCN8A, SCN2A, KCNQ3
Muscle contraction	2	51.4×	9e-04	SCN8A, SCN2A
Sensory perception of taste	1	112.0×	0.014	SCN2A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	92.8×	0.015	SCN2A
Voltage gated Potassium channels	1	81.0×	0.016	KCNQ3
Potassium Channels	1	44.8×	0.026	KCNQ3
Sensory Perception	1	31.7×	0.034	SCN2A
Neuronal System	1	14.8×	0.066	KCNQ3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle cell action potential involved in contraction	2	468.1×	2e-04	SCN8A, SCN2A
neuronal action potential	2	321.0×	2e-04	SCN2A, KCNQ3
sodium ion transport	2	181.2×	4e-04	SCN8A, SCN2A
myelination	2	167.7×	4e-04	SCN8A, SCN2A
sodium ion transmembrane transport	2	135.4×	5e-04	SCN8A, SCN2A
neuron apoptotic process	2	123.5×	5e-04	SCN2A, KCNQ3
apoptosome assembly	1	5617.3×	8e-04	KCNQ3
regulation of action potential firing threshold	1	5617.3×	8e-04	KCNQ3
intrinsic apoptotic signaling pathway in response to osmotic stress	1	2808.7×	0.001	SCN2A
substantia propria of cornea development	1	2808.7×	0.001	KCNQ3
inhibitory chemical synaptic transmission	1	1872.4×	0.002	KCNQ3
action potential initiation	1	1872.4×	0.002	KCNQ3
psychomotor behavior	1	1123.5×	0.002	KCNQ3
mitochondrial depolarization	1	802.5×	0.003	KCNQ3
membrane hyperpolarization	1	624.1×	0.004	KCNQ3
excitatory chemical synaptic transmission	1	432.1×	0.005	KCNQ3
neuron remodeling	1	401.2×	0.005	KCNQ3
nerve development	1	312.1×	0.006	KCNQ3
response to auditory stimulus	1	244.2×	0.008	KCNQ3
peripheral nervous system development	1	193.7×	0.009	SCN8A
protein targeting	1	122.1×	0.013	KCNQ3
action potential	1	119.5×	0.013	SCN8A
regulation of synaptic plasticity	1	86.4×	0.018	KCNQ3
cellular response to xenobiotic stimulus	1	80.2×	0.018	KCNQ3
cellular response to calcium ion	1	66.9×	0.021	KCNQ3
memory	1	61.1×	0.022	SCN2A
exocytosis	1	50.6×	0.025	KCNQ3
protein import into nucleus	1	48.0×	0.026	KCNQ3
potassium ion transmembrane transport	1	45.3×	0.026	KCNQ3
cellular response to hypoxia	1	40.4×	0.029	SCN2A

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 0

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN8A	IMIPRAMINE
SCN2A	BEPRIDIL
KCNQ3	FLUPIRTINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN8A	25	4
KCNQ3	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN2A, SCN8A
SERTINDOLE	4	SCN2A, SCN8A
PIMOZIDE	4	SCN2A, SCN8A
NIFEDIPINE	4	SCN2A, SCN8A
DILTIAZEM	4	SCN2A, SCN8A
MIBEFRADIL	4	SCN2A, SCN8A
HALOPERIDOL	4	SCN2A, SCN8A
MEXILETINE	4	SCN2A, SCN8A
AMITRIPTYLINE	4	SCN2A, SCN8A
AMIODARONE	4	SCN2A, SCN8A
CHLORPROMAZINE	4	SCN2A, SCN8A
TETRACAINE	4	SCN2A, SCN8A
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
KCNQ3	97	Binding:91, Functional:4, ADMET:1, Toxicity:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN8A	173
SCN2A	203

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
IMIPRAMINE	4	SCN2A, SCN8A
SERTINDOLE	4	SCN2A, SCN8A
PIMOZIDE	4	SCN2A, SCN8A
NIFEDIPINE	4	SCN2A, SCN8A
DILTIAZEM	4	SCN2A, SCN8A
MIBEFRADIL	4	SCN2A, SCN8A
HALOPERIDOL	4	SCN2A, SCN8A
MEXILETINE	4	SCN2A, SCN8A
AMITRIPTYLINE	4	SCN2A, SCN8A
AMIODARONE	4	SCN2A, SCN8A
CHLORPROMAZINE	4	SCN2A, SCN8A
TETRACAINE	4	SCN2A, SCN8A
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SCN8A, SCN2A, KCNQ3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.